1Ernest Gallo Clinic and Research Center, Department of Neurology, University of California-San Francisco, Emeryville, CA 94608, United States. rvanrijn@gallo.ucsf.edu

Abstract

BACKGROUND:

Naltrexone is one of the few drugs approved by the Federal Drug Administration for the treatment of alcoholism. However, naltrexone is only effective in a subpopulation of treatment-seeking alcohol abusers, and suffers from compliance issues. The non-selective nature of this opioid antagonist likely contributes to its side effects and poor therapeutic efficacy. Drugs selectively targeting delta opioid receptor subtypes offer a potential way to treat alcohol abuse disorders. We have recently shown that delta subtype-selective agonists TAN-67 and SNC80 can have opposing effects on alcohol consumption, while having similar effects on alcohol withdrawal-induced anxiety.

METHODS:

We studied the ability of TAN-67 and SNC80 to induce place preference in naïve and ethanol exposed C57BL/6 mice and determined the effect of these agonists on the expression of ethanol place preference.

RESULTS:

We show that TAN-67 and SNC80 have opposing actions on ethanol place preference. However, neither of the drugs induces place preference by themselves at doses that are therapeutically effective in mice. Interestingly, SNC80, like naltrexone reduces ethanol place preference, however we have previously shown that SNC80 increases ethanol consumption at the tested dose. Similar to naltrexone, TAN-67 reduces alcohol consumption, but we show here that it may be due to an increase in ethanol place preference. Importantly, we found that chronic ethanol exposure does not increase the rewarding properties of the DOR subtype selective agonists.

CONCLUSIONS:

Our results provide a better understanding of how DOR subtype selective drugs could potentially be used for treatment of alcohol abuse disorders.

The DOR agonists TAN-67 and SNC80 modulate ethanol place preference in opposite ways

C57BL/6 mice (n=12–16) were conditioned to i.p. ethanol (2 g/kg, E) or saline (S) paired with one side of a 2-chamber CPP box for five minutes per session for eight session (see drawing and methods section). On the days before (pre) and after (post) the conditioning sessions mice were allowed to freely explore both chambers of the CPP box for 30 minutes and time spent on each side was recorded. On the final test day mice were injected s.c. with either saline, 25 mg/kg TAN-67 or 20 mg/kg SNC80. Thirty minutes after injection, Mice were injected i.p. with saline and placed in the CPP apparatus. (*p<0.05; ***p<0.001)

DOR selective agonists do no produce place preference in naïve or ethanol exposed mice

A, Naive C57BL/6 mice (n=10–14) were conditioned by twice daily injection with saline (s) or drug (d) [TAN-67 (25 mg/kg), SNC80 (20 mg/kg), naltrexone (NTX, 1.5 mg/kg) or morphine (6 mg/kg)] for three days. On the days before (pre) and after (post) the conditioning sessions mice were allowed to freely explore both chambers of the place preference set up for 30 minutes and time spent on each side was recorded. B, C57BL/6 mice (n=12) were trained to self-administer ethanol in a limited access 2-bottle choice paradigm for three weeks. During the fourth week animals were conditioned in a place preference paradigm to TAN-67 (25 mg/kg) or SNC80 (20 mg/kg) as described above. (*p<0.05)